Malaria is a mosquito-borne infectious disease caused by the infection of Plasmodium via the bites of infected female anopheles mosquito or the transfusion of blood from patients carrying Plasmodium parasites. There are four Plasmodium species affecting humans, namely, Plasmodium vivax, Plasmodium malariae, Plasmodium falciparum and Plasmodium ovale. There is also a malaria which both human and monkey can suffer from and is caused by Plasmodium knowlesi. Malaria causes symptoms which mainly include intermittent attacks, fever, sweating, weakness, vomiting, and headache. As a result of long and repeated attacks, anemia and splenomegaly usually occur. Patients infected with Plasmodium falciparum can develop into cerebral malaria and even death if untreated. After many years of efforts made by the healthcare workers, the incidence of malaria in China has dropped to a very low level. According to the epidemiological surveillance made in 1992, the number of patients throughout the whole country fell to 70,000. In China, Plasmodium vivax and Plasmodium falciparum account for the majority of cases, while the other three are rare. In recent years, however, there are increasing cases imported from abroad or brought back by travelers to areas where the disease is common. Globally, nevertheless, malaria is still widespread in many countries and regions, and especially in some countries of Africa, Southeast Asia, Central America and South America. The mortality of severe cases caused by Plasmodium falciparum is extremely high. According to the statistics made by the World Health Organization (WHO) in recent years, it is estimated that there are nearly 3.4 billion people in the world at the risk of malaria transmission, of which 1.2 billion are at high risk. Malaria caused an estimated 620,000 deaths each year, of which more than 70 percent are children under 5.
Depending on the host, Plasmodium can be the species that infects humans and the species that infects other animals. The life cycle of Plasmodium infecting humans has the stage inside the human's body and the stage inside the anopheles' body; in the human's body there are the liver stage and the erythrocyte stage. The anti-malarial artemisinin invented by Chinese scientists and most of the classic anti-malarial medications such as chloroquine act during the erythrocyte stage but have no inhibitory effects on the parasites at the liver stage. Artemisinin is the most commonly used first line antimalarial drug. Chinese manufacturers provide 90% of the raw material of artemisinin. Three suppliers of the pharmaceutical drugs chosen by world health organization (WHO) are foreign companies for the reason that Chinese manufactories do not produce the kinds of artemisinin formulations for which there is a great demand by other countries. Resistance of Plasmodium to current antimalarial drugs has emerged worldwide. In addition to extensive resistance to chloroquine and sulfonamides, Plasmodium also exhibits drug resistance to the first-line antimalarial drug, i.e. the artemisinin component which is the core drug of the artemisinin-based combination therapy (Ariel, F. et al., A molecular marker of artemisinin-resistant Plasmodium falciparum malaria, Nature 505, 50-55, 2014). Primaquine is a relatively new antimalarial drug used for the liver stage. However, this drug has serious side effects. It can not only cause certain patients with malaria to suffer from acute hemolytic anemia, but also have no inhibitory effect at all on the Plasmodium falciparum of the blood stage, and thus it cannot be used as the medication to control the symptoms. There also exist such liver stage medications as Malarone consisting of atovaquone/proguanil combination. However, the drug is costly for the majority of malaria patients. Thus, the global market needs new, efficient and affordable anti-malarial drugs with low toxicity and no drug resistance to protect susceptible populations.
Decoquinate (CAS No. 18507-89-6) is a coccidiostatic drug used mainly in poultry and livestock such as cattle, horses and sheep. It is used widely in many countries of the world including China. It acts mainly in the gut to suppress the coccidia infection. In recent years, it has been found that decoquinate (DQ) has a potent inhibitory and killing effect against Plasmodium both in vitro and in vivo (Science 2011; 334: 1372-7). With respect to the anti-malarial efficacy, it has obvious advantages over the existing anti-malarial drugs (JID 2012: 205: 1278-86). It acts by inhibiting the cytochrome bc1 complex of Plasmodium mitochondria. DQ has both inhibitory effects on the development of Plasmodium during the liver stage and on the reproduction of Plasmodium during the erythrocyte stage. Whether it is used as a veterinary medicine or as a testing article in animal toxicology studies, DQ has not been found to have any significant side effects and toxicity. Studies conducted by the present inventors and other investigators have shown that DQ does not have resistance from chloroquine-resistant Plasmodium (for references: a DQ nano-formulation and its preparation and use; JID 2012: 205: 1278-86). In addition, some studies demonstrated that DQ had killing effects on neurotoxin Sarcocystis (Intern J Appl Res Vet Med. Vol. 10, No. 1, 2012) and Toxoplasma gondii (Veterinary Record, 1996 [138] 434-436).
Decoquinate with a molecular weight of 417.54, low water solubility, and high lipophilicity (log Kow value of 5.2-5.5) can be obtained by chemical synthesis. DQ is poorly absorbed by the intestine due to its water insolubility. When used as a veterinary drug against coccidiosis, it does not need to be absorbed by the intestine into the body to exert a pharmacological effect. However, the oral dosage form is still the most convenient and feasible way for administration, and therefore, in order to develop DQ as an oral form of antimalarial drugs, it is essential to solve the solubility problem for effective absorption by the intestine.
For insoluble compounds with high biological activity in vitro, methods such as making it into salt, enhancing its solubility, and reducing its particle size can be used to increase the intestinal absorption and bioavailability of the drug. A variety of attempts to make DQ into a salt to enhance its water-solubility has failed. Formulation prepared by the addition of surfactants or the reduction of particle size can increase the delivery of DQ in vivo as well as anti-malarial efficacy. However, this type of methods typically requires an organic solvent, involves multiple processes, and takes a longer period of time for subsequent manufacturing process. The preparation of a solid dispersion of DQ by hot-melt only method can solve the problem of its water insolubility to a certain extent; however, with using this sole hot-melt method, the process is cumbersome and DQ is vulnerable to thermal decomposition and cannot be easily processed into a pharmaceutical drug, and thus it is only used to manufacture DQ as a veterinary medicine.
Solid dispersion is a commonly used formulation method in which poorly soluble or water-insoluble drug molecules, including colloidal, microcrystalline or amorphous material, are uniformly dispersed in other water-soluble materials prior to the addition of water. Hot melt extrusion (HME) method is a relatively new technology developed in the field of pharmaceutical formulation in recent years in part to solve the problem of insoluble compounds. This technology takes the advantage of combination of both solid dispersion technology and mechanical preparation process. Through the process of heating at elevated controlled temperature and pressure, twin screw rotation and flow through the die, raw materials fed through a hopper are pumped through a heated barrel, mixed, sheared, melted and extruded into a product of uniform shape and density, resulting in amorphous solid dispersions. This method does not require organic solvent and can be continuously performed at a small scale or large-scale, and therefore it is not only suitable for research and development, but also for commercial production. However, heat-labile drugs or polymer carriers are not suitable for being processed using hot melt or HME method because the decomposition of drugs or excipients and the generation of related substances will reduce the efficacy and safety profile of drugs, which therefore is the main reason for avoiding the use of HME method.